DK169702B1 - Phenoxysubstituerede beta-carbolinderivater og fremgangsmåde til deres fremstilling - Google Patents
Phenoxysubstituerede beta-carbolinderivater og fremgangsmåde til deres fremstilling Download PDFInfo
- Publication number
- DK169702B1 DK169702B1 DK543886A DK543886A DK169702B1 DK 169702 B1 DK169702 B1 DK 169702B1 DK 543886 A DK543886 A DK 543886A DK 543886 A DK543886 A DK 543886A DK 169702 B1 DK169702 B1 DK 169702B1
- Authority
- DK
- Denmark
- Prior art keywords
- carboline
- methoxymethyl
- carboxylic acid
- chlorophenoxy
- ester
- Prior art date
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- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical group 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims abstract description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims abstract 2
- -1 4-methoxy-phenoxy Chemical group 0.000 claims description 182
- 150000001875 compounds Chemical class 0.000 claims description 40
- 150000002148 esters Chemical class 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- SRDUGOLOKRLITC-UHFFFAOYSA-N 4-[[3-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-methyl-9h-pyrido[3,4-b]indol-6-yl]oxy]aniline Chemical compound CCC1=NOC(C=2C(=C3C4=CC(OC=5C=CC(N)=CC=5)=CC=C4NC3=CN=2)C)=N1 SRDUGOLOKRLITC-UHFFFAOYSA-N 0.000 claims description 2
- GCKDPKYNCRZCOG-UHFFFAOYSA-N 5-[5-(4-chlorophenoxy)-4-methyl-9h-pyrido[3,4-b]indol-3-yl]-3-ethyl-1,2,4-oxadiazole Chemical compound CCC1=NOC(C=2C(=C3C4=C(OC=5C=CC(Cl)=CC=5)C=CC=C4NC3=CN=2)C)=N1 GCKDPKYNCRZCOG-UHFFFAOYSA-N 0.000 claims description 2
- ORHBANOVLURKKP-UHFFFAOYSA-N 5-[6-(2,4-dichlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indol-3-yl]-3-ethyl-1,2,4-oxadiazole Chemical compound CCC1=NOC(C=2C(=C3C4=CC(OC=5C(=CC(Cl)=CC=5)Cl)=CC=C4NC3=CN=2)COC)=N1 ORHBANOVLURKKP-UHFFFAOYSA-N 0.000 claims description 2
- CAJDBSWZROJJPP-UHFFFAOYSA-N 5-[6-(4-chlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indol-3-yl]-3-ethyl-1,2,4-oxadiazole Chemical compound CCC1=NOC(C=2C(=C3C4=CC(OC=5C=CC(Cl)=CC=5)=CC=C4NC3=CN=2)COC)=N1 CAJDBSWZROJJPP-UHFFFAOYSA-N 0.000 claims description 2
- SLYDYLLJUXFULK-UHFFFAOYSA-N Gedocarnil Chemical compound C=12C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=CC=1OC1=CC=C(Cl)C=C1 SLYDYLLJUXFULK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- GUPVUSNIMOUYNX-UHFFFAOYSA-N ethyl 5-(2-chloro-4-nitrophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C3=C(COC)C(C(=O)OCC)=NC=C3NC2=CC=CC=1OC1=CC=C([N+]([O-])=O)C=C1Cl GUPVUSNIMOUYNX-UHFFFAOYSA-N 0.000 claims description 2
- KDYOHVCEILTVQR-UHFFFAOYSA-N ethyl 6-(4-chlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C3=C(COC)C(C(=O)OCC)=NC=C3NC2=CC=C1OC1=CC=C(Cl)C=C1 KDYOHVCEILTVQR-UHFFFAOYSA-N 0.000 claims description 2
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims 1
- SVQZRISZGDYYOG-UHFFFAOYSA-N ethyl 4-(methoxymethyl)-5-(4-nitrophenoxy)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C3=C(COC)C(C(=O)OCC)=NC=C3NC2=CC=CC=1OC1=CC=C([N+]([O-])=O)C=C1 SVQZRISZGDYYOG-UHFFFAOYSA-N 0.000 claims 1
- IYWXNDPCGMXRQC-UHFFFAOYSA-N ethyl 5-(2,4-dichlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C3=C(COC)C(C(=O)OCC)=NC=C3NC2=CC=CC=1OC1=CC=C(Cl)C=C1Cl IYWXNDPCGMXRQC-UHFFFAOYSA-N 0.000 claims 1
- HABCXLIGUSCNJM-UHFFFAOYSA-N propan-2-yl 5-(2-chlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=CC=1OC1=CC=CC=C1Cl HABCXLIGUSCNJM-UHFFFAOYSA-N 0.000 claims 1
- BARANMZFMYADFX-UHFFFAOYSA-N propan-2-yl 6-(3-chlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=CC(Cl)=C1 BARANMZFMYADFX-UHFFFAOYSA-N 0.000 claims 1
- ZJUVWPFQSQLERH-UHFFFAOYSA-N propan-2-yl 6-(4-chlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=C(Cl)C=C1 ZJUVWPFQSQLERH-UHFFFAOYSA-N 0.000 claims 1
- DMSVMEAKDMUTMV-UHFFFAOYSA-N tert-butyl 4-(methoxymethyl)-5-phenoxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C=3C(COC)=C(C(=O)OC(C)(C)C)N=CC=3NC2=CC=CC=1OC1=CC=CC=C1 DMSVMEAKDMUTMV-UHFFFAOYSA-N 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 2
- 125000002252 acyl group Chemical group 0.000 abstract 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 2
- 125000005530 alkylenedioxy group Chemical group 0.000 abstract 1
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- 238000002844 melting Methods 0.000 description 5
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- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
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- 241000699670 Mus sp. Species 0.000 description 4
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- IOWRSFQKLLMQSG-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-6-(3-methoxyphenoxy)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=CC(OC)=C1 IOWRSFQKLLMQSG-UHFFFAOYSA-N 0.000 description 1
- OHCWUJWZRJEYBD-UHFFFAOYSA-N propan-2-yl 6-(2-cyano-3-fluorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=CC(F)=C1C#N OHCWUJWZRJEYBD-UHFFFAOYSA-N 0.000 description 1
- QHQWXAVTYHABIC-UHFFFAOYSA-N propan-2-yl 6-(3,4-dichlorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=C(Cl)C(Cl)=C1 QHQWXAVTYHABIC-UHFFFAOYSA-N 0.000 description 1
- OQPKUIPIMCWRJN-UHFFFAOYSA-N propan-2-yl 6-(3,5-dichloro-2-nitrophenoxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate Chemical compound CC(C)OC(=O)C1=NC=C2C(=C1COC)C3=C(N2)C=CC(=C3)OC4=C(C(=CC(=C4)Cl)Cl)[N+](=O)[O-] OQPKUIPIMCWRJN-UHFFFAOYSA-N 0.000 description 1
- PJTBJSFOGKTWGN-UHFFFAOYSA-N propan-2-yl 6-(3-cyanophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=CC(C#N)=C1 PJTBJSFOGKTWGN-UHFFFAOYSA-N 0.000 description 1
- PKIFJOKHLMTZNR-UHFFFAOYSA-N propan-2-yl 6-(4-fluorophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=C(F)C=C1 PKIFJOKHLMTZNR-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Photoreceptors In Electrophotography (AREA)
Description
i DK 169702 B1
Opfindelsen angår hidtil ukendte phenoxysubst i tuerede j5-carbo-linderivater og en fremgangsmåde til deres fremstilling.
Fra EP-A-130.140 kendes 6-(4-methoxyphenoxy)-4-methoxymethy1 -5 β-carbolin-3-carbonsyreethy1 esteren, og fra EP-A-54.507 kendes 5-phenoxy-4-methy 1 -)3-c ar bol i n-3-carbonsyreethyl esteren, hvilke forbindelser har den fra β-carboli ner kendte virkning på centralnervesystemet .
10 Forbindelserne ifølge opfindelsen har den almene formel I
R4
H
hvor 20 X er en oxadiazoly1 rest med formlen O—N ^“=1 B2
“(\ I 7 eller v ¥_Lr2 N-O
25 hvor r2 betyder lavere alkyl eller C3_7cykloalkyl eller X er en C00R3-gruppe, hvor R3 betyder lavere alkyl, og R4 er hydrogen, lavere alkyl eller lavere alkoxyalkyl, og 30
Ri optræder en eller flere gange og er hydrogen, halogen, lavere alkyl, lavere alkoxy, Ci-^alkanoyl, cyano, nitro, lavere alkoxycarbonyl, SO2R6, hvor R® betyder lavere alkyl, eller -NH2, idet 35 /7Λ X ikke er COOEt, når grupperne R*—)—O— og R4 2 DK 169702 B1 betyder henholdsvis 5-phenoxy og methyl, eller 6-(4-methoxy-phenoxy) og methoxymethy1.
Disse forbindelser har en væsentligt forbedret antikonvulsiv 5 virkning i sammenligning med de ovenfor nævnte kendte forbindelser.
De hidtil ukendte β-carboli nderivater med den almene formel I kan være substitueret en eller to gange i A-ringen i stilling 10 5-8, idet substitution i 5- eller 6-stilling foretrækkes.
Substituenten Ri kan optræde en eller flere gange ens eller forskelligt på arylresten, fortrinsvis 1-3 gange.
15 Ved lavere alkyl skal forstås både ligekædede og forgrenede rester med C^-gcarbonatomer. For eksempel skal nævnes de foretrukne Ci_4alkylrester såsom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl og tert.-butyl og sek.-butyl.
20 Cykloalkylresten R2 kan indeholde 3-7 carbonatomer, idet der som foretrukne rester med 3-5 carbonatomer skal nævnes f.eks. cyklopropyi# methyIcyklopropyl, cyklobutyl, cyklopen-tyl og andre.
25 Alkanoyl afledes af alifatiske carbonsyrer med indtil 4 carbonatomer som f.eks. myresyre, eddikesyre, propionsyre, smørsyre og andre.
Ved halogen skal forstås fluor, chlor, brom og jod.
30
Forbindelserne ifølge opfindelsen viser overraskende, sammen-1 i g net med de tidligere kendte jS-carboliner, ved den farmakologiske prøve overlegne psykotrope egenskaber, således som det kan ses af tabel len med nogle forbindelser ifølge opfindelsen 35 som eksempel.
Forbindelserne ifølge opfindelsen viser i sær anxiolytisk og antikonvulsiv virkning. Til undersøgelse af den anti konvu1 s i ve 3 DK 169702 B1 virkning blev undersøgt ophævelsen af de med pentylentetrazol (Pentazol) inducerede kramper. Pentazol indgives i en mængde på 150 mg/kg som saltsyreopløsning (pH 2-3) subkutant 15 -30 minutter efter den intraperitoneale applikation af forsøgs-5 stoffet. Denne mængde inducerer kloniske og toniske kramper, som hos ubehandlede dyr fører til døden. Antallet af mus, der udviser kramper, og antallet af dem, som er døde 30 minutter efter indgivelse af Pentazol, registreres (PZT-krampe antago-ni sme) .
10
De i tabellen anført EDsø-værdier blev bestemt ved metoden ifølge Litchfield & Wilcoxon (J. Pharmacol. Exp. Ther. 96 (1949) 99-103) som den mængde af det antagonistisk virkende stof, som beskytter 50% af dyrene mod kramper og død.
15
TABEL
R4 R -
H
25
PTZ
IC50 ed50 (ed50) tpV 0- 4 (ng/ml) (mg/kg) (mg/kg) —' κ X in vitro in vivo in vivo 30 ------------------------------------------------------------- 6-(p-OCH3-phenoxy)* CH20CH3 COOEt 0,29 0,43 8 5-phenoxy** CH3 COOC2H5 2,0 2,8 >30
O—N
5-(2-C1-phenoxy) CH2OCH3 / I 3,1 11 0,8 35 ^r-IL-Et 5“(2-Cl-phenoxy) CH2OCH3 -COOCH(CH3)2 2,6 19 4 phenoxy fiChl0r~ εΗ2°°Η3 -COOC2H5 2'9 3,2 4 4 DK 169702 B1 TABEL (fortsat)
PTZ
IC,n SD ÆD--) ___ 50 DU D v - /oV °- 4 (ng/ml) (mg/kg) img/kg)
Rl^—1' R X in vitro in vivo in vivo 6- (2-nitrophenoxy) CH20CH3 -COOCH(CH3)2 0,33 1,8 13 phin0xy)n°"3"C1~ CH2OCH3 -COOCHICI^ 0,67 3,0 1 10 6- (2-cyanophenoxy) CH20CH3 -COOCH(CH3)2 0,29 3,8 4
O —N
β-(4-acetylphenoxy)CH2OCH3 0,45 7,7 0,3 N-LEt 5-phenoxy CH_OCH, -COOEt 0,3 0,4 18 15 li
O— N
5-phenoxy CH2OCH3 "V\| 0,6 0,3 0,1 N-LEt
O—N
5- phenoxy CH3 / | 4,3 3,9 2 o« N—!—Et 20
O— N
/ 6- phenoxy CH, “\\ 3,2 2,6 2,4 N-1—Et 25 5-(3-Cl-Phenoxy) * CH^OCH —<T° il ® · * H 0»8 2 3 N —Et 5(3-Cl-Phenoxy) CH2OCH3 COOCHiCH.^ 2,6 19 4 30 35 5 DK 169702 B1 TABEL (fortsat^
PTZ
/TV IC50 ' ED50 :EB50; - ύ8Τ°- r4 (ng/ml) (mg Ag) {mg/kg; R X in vitro in vivo in vivo 6-(2-Methylphenoxy) CH2OCH3 COOCH(CH3)2 ^ 3 g, 9 0,5 10 6-^3-Cl- 4-N02-phenoxy) CH2OCH3 C00CH(CH3)2 0,69 2,4 2 6-(2-NO -phenoxy) CHo0CHo—<^N « 0,7 1,6 1 2 2 3 —Ι_Λ 6-(2-CH30-phenoxy) CH2OCH3 -COOCH(CH3)2 0,49 0,92 0,9 15
O-N
6-(4-CH SO -phenoxy) CH OCH Il 0,3 11,3 2
2 3 n-iLc.H
2 5
6-Phenoxy H O-N
-< II
N-U—1,5 1,3 4 20
6-(4-NH0-Phenoxy) CH_ .0-N
3 -< II
N-Lch 0,8 0,41 1 ^ 5 5-(2-Isopropoxy-carbonyl- CH„OCH- COOCH(CH_)„ „ „„ phenoxy) 23 3 2 0,96 10 4 25 * Forbindelse kendt fra EP 130.140 ** Forbindelse kendt fra EP 54.507.
30 Det er kendt, at bestemte steder i centralnervesystemet hos hvirveldyr har en høj specifik affinitet til binding af 1,4- og 1,5-benzodiazepiner (R.F.Squires & C.Braestrup, Nature (London) 266 (1977), 734). Disse steder kaldes benzodiazepin-receptorer.
35 De farmakologiske egenskaber af forbindelserne ifølge opfindelsen blev bestemt ved undersøgelse af fortrængningsevnen af radioaktivt mærket flunitrazepam fra benzodiazepin-receptorerne.
. 6 DK 169702 B1
Fortrængningsaktiviteten af forbindelserne ifølge opfindelsen angives som IC50~værdi og ED^Q-værdi. IC^Q-værdien angiver den koncentration, som bevirker en 50% fortrængning af den specifikke binding af H3-flunitrazepam (1,0 nM, 0°C) i prøver med et 5 samlet rumfang på 0,55 ml af en suspension af hjernemembraner, f.eks. fra rotter.
Fortrængningsprøven udføres som følger:
0,5 ml af en suspension af ubehandlet rotteforhjerne i 25 mM
KH2P04, pH = 7,1 (5 - 10 mg væv/prøve), inkuberes i 40 - 60 mi- 10 nutter ved 0°C sammen med H3-diazepam (specifik aktivitet 3 14,4 Ci/mmol, 1,9 nM) eller H -flunitrazepam (specifik aktivitet 87 Ci/mmol, 1,0 nM). Efter inkubation filtreres suspensionen gennem en glasfritte, rémanensen vaskes to gange med kold stødpudeopløsning, og radioaktiviteten måles i scintillations-15 tæller.
Forsøget gentages så, men således, at der før tilsætningen af det radioaktivt mærkede benzodiazepin tilsættes en bestemt mængde eller en overskydende mængde af den forbindelse, hvis fortrængningsaktivitet skal bestemmes. På grundlag af de fremkomne vær-20 dier kan ICj-g-værdien beregnes.
EDj-g-værdien er den dosis af et forsøgsstof, som bevirker en reduktion af den specifikke binding af flunitrazepam til benzo-diazepinreceptoren i en levende hjerne til 50% af kontrolværdien.
25 In vivo prøven udføres som følger:
Grupper af mus får injiceret forsøgsstoffet i forskellige doser, normalt intraperitonealt. Efter 15 minutter får musene intra- 3 venøst indgivet H -flunitrazepam. Efter yderligere 20 minutter 7 DK 169702 B1 dræbes musene. Deres forhjerne udtages, og den til hjernemembra-nen specifikt bundne radioaktivitet måles ved scintinations-tælling. ED^Q-værdien bestemmes af kurven over dosis/virkning.
De hidtil ukendte forbindelser med den almene formel I har værdi-5 fulde farmakologiske egenskaber. Især virker de på centralnervesystemet og er derfor egnede som psykofarmaka i humanmedicinen, idet de især anvendes til behandling af angst ledsaget af depressioner, epilepsi, søvnforstyrrelser, spasticiteter og muskel-afslapninger under anæstesi. Også amnestiske eller hukommelses-10 fremmende egenskaber findes hos forbindelserne ifølge opfindelsen.
Forbindelserne ifølge opfindelsen kan anvendes til sammensætning af farmaceutiske præparater, f.eks. til oral og parenteral anvendelse til mennesker på i og for sig kendte måder inden for galenikken.
15 Som hjælpestoffer til sammensætning af farmaceutiske præparater egner sig fysiologisk anvendelige organiske og uorganiske bærerstoffer, der er egnede til enteral og parenteral anvendelse, og som er indifferente over for forbindelserne ifølge opfindelsen.
Som bærerstoffer skal f.eks. nævnes vand, saltopløsninger, alkoho-20 ler, polyethylenglycoler, polyhydroxyethoxyleret ricinusolie, gelatine, lactose, amylose, magniumstearat, talkum, kiselsyre, fedtsyremono- og diglycerider, pentaerythritfedtsyreester, hydroxymethylcellulose og polyvinylpyrrolidon.
De farmaceutiske præparater kan steriliseres, og/eller der kan 25 tilsættes hjælpestoffer såsom smøremidler, konserveringsstoffer, stabilisatorer, befugtningsmidler, emulgatorer, stødpude- og farvestoffer.
Til parenteral anvendelse egner sig især injektionsopløsninger 8 DK 169702 B1 eller suspensioner, især vandige opløsninger af de aktive forbindelser i polyhydroxyethoxyleret ricinusolie.
Til oral anvendelse egner sig især tabletter, drageer eller kapsler med talkum og/eller en kulbrintebærer eller et kulbrinte-5 bindemiddel såsom f.eks. lactose, majsstivelse eller kartoffelstivelse. Anvendelsen kan også ske i flydende form, f.eks. som saft, hvortil der eventuelt sættes et sødestof.
Forbindelserne ifølge opfindelsen indføres i en fysiologisk anvendelig bærer i en dosisenhed på 0,05 - 100 mg aktivt stof.
10 Forbindelserne ifølge opfindelsen anvendes i en dosis på 0,1 -300 mg pr. dag, fortrinsvis 1-30 mg/dag.
Fremstillingen af forbindelserne ifølge opfindelsen med den almene formel I sker på i og for sig kendte måder.
Eksempelvis sker fremstillingen af forbindelsen med den almene for-15 mel I ved, at man
a) Omsætter en forbindelse med den almene formel II
R4 (II)
H
1 4 hvor R og R har ovennævnte betydning, med en forbindelse med formlen 9 DK 169702 B1
9 ^ NOH
R - XNH2 2 hvor R har den ovennævnte betydning, til en forbindelse med den almene formel I, hvori X er resten -q , N--R^ 2 hvor R har den ovennævnte betydning,
b) omsætter en forbindelse med den almene formel III
' ' R4
T ^NOH
jjø)—·NHz (iii) v
H
5 hvor 1 4 R og R har ovennævnte betydninger, med et carbonsyreanhydrid 2 2 (R CO) 2*3, hvor R har den ovennævnte betydning, til en forbindelse med den almene formel I, hvori X er resten
-C=U
2 hvor R har den ovennævnte betydning,
10 c) omsætter en forbindelse med den almene formel IV
10 DK 169702 B1 R4 C00r3 ho +oi 1O i \/\ (IV)
H
3 4 hvor R og R har ovennævnte betydninger, med en forbindelse med formlen R1 -1' 1 1' hvor R har ovennævnte betydning, og R er en elektronfjernende substituent, og eventuelt derefter 5 a) reducerer en nitrogruppe til aminogruppen og om ønsket des-amiherer den således fremkomne aminogruppe eller ombytter den med halogen, eller β) hvis R1 er halogen, katalytisk dehalogenerer eller γ) omestrer eller forsæber en estergruppe* 10
Hal betyder halogen, fortrinsvis fluor og chlor.
Med henblik på indføring af l,2,4-oxadiazol-5-ylresten, bliver β-carbolincarbonsyren med den almene formel .II bragt til kondensation med en amidoxim med formlen 11 ' DK 169702 B1 R2 - C(=NOH)NH2 i et indifferent opløsningsmiddel, der koger over 100°C og er indifferent over for reaktionsdeltagerne, ved reaktionsblandingens tilbagesvalingstemperatur. Egnede opløsningsmidler til kondensationsreaktionen er f.eks. toluen og dime thy lf omamid. Hensigts-5 mæssigt bliver den frie £-carbolin-3-carbonsyre aktiveret på egnet måde før kondensationsreaktionen. Til dette formål kan den frie syre omdannes, f.eks. til det blandede anhydrid, til den aktiverede ester eller til chloridet.
Velegnet har vist sig også en aktivering til imidazolid med imid-10 azol/thionylchlorid eller også carbonyldiimidazol i et aprot opløsningsmiddel såsom dioxan, tetrahydrofuran, dimethylformamid eller N-methylpyrrolidon ved temperaturer mellem 0 og 50°C, fortrinsvis stuetemperatur.
Med henblik på indføring af 1,2,4-oxadiazol-3-yl-resten emsætter 15 man f.eks. 3-carbonsyrenitrilen med hydroxylamin til forbindelsen med den almene formal III. Den således fremkomne 3-carbolin-3- carboxamidoxim får ved stuetemperatur tilsat syreanhydridet 2 (R CO)20) og opvarmes derefter til kogetemperaturen. Reaktionen er færdig efter ca. 7 timer og oparbejdes på sædvanlig måde.
20 Indføringen af phenoxyresten sker fortrinsvis ved omsætning af forbindelsen med den almene formel IV med et fluorbenzenderivat, som hensigtsmæssigt bærer en yderligere elektronfjernende substituent .
i «
Som elektronfjernende substituenter R skal f.eks. nævnes de 25 følgende for R1 anførte rester: nitro, lavere alkoxycarbonyl, lavere alkylsulfonyl, trifluormethyl, cyano etc.
Omsætningen med det substituerede halogenbenz’énderivat udføres i 12 DK 169702 B1 basisk medium i dipolære aprote opløsningsmidler ved temperaturer indtil opløsningsmidlets kogepunkt.
Som opløsningsmiddel egner sig f.eks. dimethylformamid, dimethyl-sulfoxid, dimethylacetamid, n-methyIpyrrolidinon, hexamethyl-5 phosphorsyretriamid og andre.
Som baser kan der bl.a. være tale om alkaliforbindelser som f.eks. natrium- eller kaliumhydroxid, natrium- eller kaliumcarbonat, eventuelt også i nærværelse af faseoverføringskatalysatorer som f.eks. kroneethere såsom 18-krone-6, dicyklohexyl-18-krone-6, 10 dibenzo-18-krone-6 eller Aliguat 336.
Hensigtsmæssigt arbejdes under en indifferent gasatmosfære, f.eks. nitrogen eller argon.
Reduktionen af nitrogruppen til aminogruppen sker f.eks. katalytisk i polære opløsningsmidler ved stuetemperatur.
15 Fortrinsvis anvendes som katalysator palladium på en bærer såsom carbon eller platin i findelt form. Til forbindelser med halogen anvender man fortrinsvis som katalysator Raney-nikkel.
Alle indifferente opløsningsmidler er egnede til reduktionen, f.eks. alkoholer eller ethere såsom methanol, ethanol, diethyl-20 ether, tetrahydrofuran eller blandinger heraf.
Hydreringen kan foretages under normaltryk eller H2-tryk.
Desamineringen sker f.eks. ved den fra litteraturen kendte Sandmeyer-fremgangsmåde. Ved denne bliver den med et nitrit intermediært frembragte diazoniumforbindelse indkogt reduktivt 25 ved forhøjet temperatur i nærværelse af kobber(I)oxid og phosphor-undersyrling.
'13 DK 169702 B1
Indføringen af halogenerne chlor, brom eller jod via amino-gruppen kan eksempelvis ske ifølge Sandmeyer, idet man omsætter de med nitriter intermediært dannede diazoniumsalte med Cu(I)-chlorid eller Cu(I)bromid i nærværelse af den tilsvarende syre, 5 saltsyre eller brombrintesyre, eller omsætter med kaliumjodid.
Indføring af fluor kan f.eks. ske ved Balz Schniemann-reaktion af diazoniumtetrafluorboratet.
Indføring af azidogruppen sker via Sandmeyer-reaktion af diazonium-saltet med f.eks. alkaliazid.
10 Den katalytiske dehalogenering udføres f.eks. med palladium-på-carbon (10%) under tilsætning af organiske baser, f.eks. tri-ethylamin, bl.a. i alkoholer.
For at undgå omestringer tager man hensigtsmæssigt esterkomponentens alkohol som opløsningsmiddel.
15 Hvis en omestring ønskes, kan man f.eks. omsætte med den tilsvarende alkohol eller alkalialkoholat, og eventuelt kan man tilsætte titantetraisopropylat som katalysator i vandfri alkohol. Sædvanligvis udføres omestringen ved temperaturer på 60 - 120°C, og den er afsluttet efter ca. 2-6 timer.
20 Indføringen af den tertiære butylestergruppe sker f.eks. ved omsætning af carbonsyren med tert.-butoxy-bis-dimethylaminomethan.
I almindelighed udføres reaktionen under en indifferent gasatmosfære såsom argon eller nitrogen og under udelukkelse af fugtighed ved forhøjet temperatur.
25 Således kan forsæbning af estergruppen ske surt eller alkalisk. Fortrinsvis forsæbes alkalisk, idet esteren opvarmes til temperaturer indtil reaktionsblandingens tilbagesvalingstemperatur 14 DK 169702 B1 sammen med fortyndet vandig alkalilud såsom kalium- eller natriumhydroxid i et protisk opløsningsmiddel, f.eks. methanol, ethanol eller ethylenglycol.
Carbonsyreamider fås f.eks. ved omsætning med aminer af de til-5 svarende imidazolider, der fremstilles intermediært af carbon- syrerne og carbonyl- eller thionyldiimidazol. Reaktionen udføres ved stuetemperatur i dipolære aprote opløsningsmidler, f.eks. dimethylformamid, dimethylacetamid og andre.
Fremstillingen af udgangsforbindelserne er kendt og sker efter 10 kendte fremgangsmåder som f.eks. beskrevet i EP-A-130140.
Således kan esterne fremstilles ved aktivering af den tilsvarende syre og påfølgende omsætning med den ønskede alkohol.
De følgende eksempler skal nærmere belyse fremgangsmåden ifølge opfindelsen.
15 EKSEMPEL 1.
5-(4-chlorphenoxy)-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-4-methoxy-methyl-3-carbolin.
5,74 g 5-(-4-chlorphenoxy) -4-methoxymethyl-|3-carbolin-3-carbonsyre opløses i 150 ml absolut dimethylformamid, der tilsættes 2,91 g 20 carbonyldiimidazol og omrøres i 3 timer ved stuetemperatur. Til denne opløsning sætter man 3,96 g propionamidoxim, omrører i 8 timer, tilsætter endnu 1 g propionamidoxim og omrører ligeledes i 8 timer. Efter inddampning i oliepumpevakuum optages der i toluen og koges i 8 timer under tilbagesvaling. Efter inddampning kro-25 matograferes to gange over kiselgel, først med methylenchlorid: ethanol (10:1) og derpå med hexan.:.acetone (1:1) som elueringsmid- ‘15 DK 169702 B1 del. Efter omkrystallisation af eddikeester/hexan og tørring over phosphorpentoxid ved 80°C i vakuum får man 2,2 g 5-(4-chlor-phenoxy) -3- (3 -ethyl-1,2,4-oxadiazol-5-yl) -4-methoxymethyl-8-carbolin med smeltepunktet 170°C.
5 På analog måde fremstilles: 5-phenoxy-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 245 - 248°C), 5- (4-nitrophenoxy)- 3- (3-ethyl-l,2,4-oxadiazol-5-yl) -β-carbolin (smeltepunkt 290°C), 10 5-(4-chlorphenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β- carbolin (smeltepunkt 193 - 194°C), 6- (4-acetylphenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin, 15 (smeltepunkt 213 - 216°C), 5-(4-nitrophenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 287°C), 5-(4-nitrophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-20 5-yl)-β-carbolin (smeltepunkt 125 - 180°C), 5-phenoxy-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 168 - 171°C), 16 " 6-phenoxy-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 205 - 208°C), DK 169702 B1 6-phenoxy-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 247 - 250°C), 5 6-(4-nitrophenoxy)-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 288 - 294°C) , 6-(4-aminophenoxy)-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 207 - 210°C), 6-(4-chlorphenoxy)-4-methyl-3-(3-ethyl-l, 2,4-oxadiazol-5-yl)-β-10 carbolin (smeltepunkt 245 - 250°C), 6-(4-nitrophenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 250 - 258°C), 15 6-(4-aminophenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β- carbolin (smeltepunkt 245 - 255°C), 6-(4-chlorphenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin 20 (smeltepunkt 178 - 192°C), 6-(4-chlorphenoxy)-4-methoxymethyl-3-(3-cyklopropyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 192 - 193°C), 6-(4-bromphenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-25 yl)-β-carbolin (smeltepunkt > 2 8 0°C), 6-phenoxy-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β- carbolin (smeltepunkt 164°C), 17 DK 169702 B1 6-(4-nitrophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5 5-yl)-β-carbolin (smeltepunkt 223 - 225°C), 6-(4-nitrophenoxy)-4-methoxymethyl-3-(3-cyklopropyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 226°C), 10 6- (2-nitrophenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2,4-ox.adiazol- 5- yl)-β-carbolin (smeltepunkt 206 - 211°C), 6- (2-nitrophenoxy)-4-methoxymethyl-3-(3-cyklopropyl-l,2,4-oxadiazol-5-yl)-β-carbolin 15 (smeltepunkt 154 - 155°C), 6-(4-aminophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5 —yI)-β-carbolin (smeltepunkt 249 - 255°C), 6-(2-methyl-4-nitrophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-2 0 oxadiazol-5-yl)-β-carbolin (smeltepunkt 2 08 - 209°C) , 18 DK 169702 B1 6-(4-diethylsulfamoylphenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-5 oxadiazol-5-yl)-β-carbolin (smeltepunkt 184 - 189°C), 6-(4-methylsulfonylphenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 150°C) , 10 6- (4-ethoxycarbonylphenoxy) -4-methoxymethyl-3- (3-ethyl-l, 2 ,.4- oxadiazol-5-yl)-β-carbolin (smeltepunkt 185 - 191°C), 6-(2-chlorphenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol- 5- yl)-β-carbolin 15 (smeltepunkt 158 - 161°C), 6- (4-cyanophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol- 5- yi)-β-carbolin (smeltepunkt 224 - 225°C), 6- (2-chlor-4-nitrophenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4- 20 oxadiazol-5-yl)-β-carbolin (smeltepunkt 200 - 213°C), 6-(2-chlor-4-aminophenoxy)-4-methoxymethy1-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-β-carbolin (smeltepunkt 235 - 247°C), 25 6-(2,4-dichlorphenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol- 5-yl)-β-carbolin (smeltepunkt 160 - 174°C), 6-(4-fluorphenoxy)-4-methoxymethy1-3-(3-ethyl-l,2,4-oxadiazol- 5-yl)-(3-carbolin (smeltepunkt 240 - 242°C) og 19 DK 169702 B1 5- (3-chlorphenoxy) -4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl) -5 β-carbolin (smeltepunkt 170 - 172°C).
EKSEMPEL 2.
4-methoxymethyl-5-phenoxy-3(3-(5-ethyl-l,2,4-oxadiazol)-yl)-3-carbolin.
0,7 itiM 4-methoxymethyl-5-phenoxy-3-carbolin-3-carboxamidoxim 10 og 1 ml propionsyreanhydrid omrøres i 2 timer ved 20°C og derefter i 5 timer ved 120°C. Efter inddampning tilsættes 10 ml tetrahydrofuran, reaktionsblandingen får lov at henstå natten . over og koncentreres så i vakuum, og reaktionsproduktet ekstra-heres med 30 ml methylenchlorid som et olieagtigt stof.
15 Udgangsmaterialet fremstilles som følger: a) 5-phenoxy-4-methoxymethyl-3-carbolin-3-carboxamid.
Til en opløsning af 30 mM thionyldiimidazol i 150 ml tetrahydrofuran sættes 2,7 g 5-phenoxy-4-methoxymethyl-3-carbolin- 3-carbonsyre. Reaktionsblandingen omrøres i 5 timer og filtre-20 res. Filtratet tilsættes 12 ml 25% NH3 i vand, der omrøres natten over og inddampes i vakuum til 50 ml. Efter tilsætning af 100 ml vand fås 2 g af det ønskede produkt som gule krystaller.
b) 5-phenoxy-3-cyano-4-methoxymethyl-(3-carbolin.
25 Til en omrørt opløsning af 1,8 g (15 mM) triphenylphosphin • 20 DK 169702 B1 i 50 ml methylenchlorid dryppes ved 0°C 1,1 g Br^ i 10 ml methylen-chlorid. Derefter tilsættes 2 g 5-phenoxy-4-methoxymethyl-|3-carbolin-3-carboxamid og 1,9 ml triethylamin. Reaktionsblandingen omrøres ved 0°C i en time og omrøres derefter kraftigt med 5 25 ml methylenchlorid og 25 ml vand i 5 minutter. Efter fjernel se af den vandige fase får man af den organiske fase ved ind-dampning 0,8 g af det ønskede produkt.
c) 4-methoxymethyl-5“phenoxy“3“carbolin-3-carboxamidoxim.
En blanding af 329 mg (0,001 mol) 3-cyano-4-methoxymethyl-5-phen-10 oxy-8-carbolin, 100 mg hydroxylamin-hydrochlorid, 20 ml ethanol (99%) og 0,52 ml af en 20% vandig kaliumcarbonatopløsning holdes under tilbagesvaling i 22 timer. Reaktionsblandingen filtreres, og filtratet inddampes. Til remanensen sættes 10 ml vand, og det krystallinske faste stof frafiltreres og vaskes med vand.
15 EKSEMPEL 3.
5- (4-nitrophenoxy) - 4 -methoxyme thy 1 -(3 -c arbol in- 3 -carbons yre -ethylester.
6 g 5-hydroxy-4-methoxymethyl-(3-carbolin-3-carbonsyreethylester under nitrogen i 200 ml dimethylformamid tilsættes 5,5 g vandfri 20 kaliumcarbonat, og der omrøres i en time ved stuetemperatur.
Efter tilsætning af 2,8 g 4-fluornitrobenzen opvarmes i 2 timer til en badtemperatur på 100°C. Efter yderligere tilsætning af 1,4 g 4-fluornitrobenzen opvarmes i 45 minutter til 100°C. Efter afkøling hældes på is og frasuges. Filterkagen kromatograferes 25 over kiselgel med acetoneihexan (1:1) som løbemiddel. Man får 5,7 g (70% af det teoretiske) 5-(4-nitrophenoxy)-4-methoxymethyl-|3-carbolin-3-carbonsyreethylester med smeltepunkt 231 - 232°C.
21 DK 169702 B1 På analog måde fremstilles: 5- (2-nitrophenoxy) -4-methyl-3-carbolin-3-carbonsyreethylester (smeltepunkt 241 - 242°C), 5- (2-nitrophenoxy)-4-ethyl-|3-carbolin-3-carbonsyreethy lester, 5 6-3(4-cyanophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- ethyle ster (smeltepunkt 226 - 227°C), 6- (2-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-isopropylester 10 (smeltepunkt 147 - 150°C), 6- (2-formylphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- isopropylester (smeltepunkt 188 - 192°C), 6- (2-cyanophenoxy) -4-methoxymethyl-|3-carbolin-3-carbonsyre-15 isopropylester (smeltepunkt 170°C), 6-(2-cyano-3-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- isopropylester (smeltepunkt 117 - 125°C), 20 6-(2-acetylphenoxy)-4-methoxymethyl-8-carbolin-3-carbonsyre- isopropylester (smeltepunkt 112 - 117°C), 6-(2-cyano-4-fluorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-isopropylester 25 (smeltepunkt 228 - 230°C), 6-(4-acetylphenoxy)-4-methoxymethyl-p-carbolin-3-carbonsyre- isopropylester (smeltepunkt 233°C), 22 DK 169702 B1 5- (4-nitrophenoxy) -4-methyl-p-carbolin--3-carbonsyreethylester 5 (smeltepunkt 225°C), 5- (4-nitrophenoxy) -4-ethyl-|3-carbolin-3-carbonsyreethy lester (smeltepunkt 217 - 218°C), 5-(4-nitrophenoxy)-p-carbolin-3-carbonsyreethylester (smeltepunkt >242°C), 10 5- (4-nitro-2-chlorphenoxy) -4-methoxymethyl-p-carbolin-3-carbon- syreethylester, 5- (4-nitro-3-methylphenoxy) -4-methoxymethyl-3-carbolin -3-carbonsyre-ethylester (smeltepunkt 212 - 213°C), 15 5-(4-nitro-2-methylphenoxy)-4-methoxymethyl-p-carbolin-3-carbon- syreethylester (smeltepunkt 190 - 192°C), 5- (4-ethoxycarbonylphenoxy) -4-methoxymethyl-f3-carbolin-3-carbonsyre-ethylester 20 (smeltepunkt 157°C), 6- (4-nitrophenoxy)-8-carbolin-3-carbonsyremethylester, 6-(4-nitrophenoxy)-p-carbolin-3-carbonsyreethylester (smeltepunkt ^250°C), 6-(4-nitrophenoxy)-4-methyl-3-carbolin-3-carbonsyreethylester (smeltepunkt 288 - 292°C), 23 DK 169702 B1 6-(4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyreethyl-ester 5 (smeltepunkt 231 - 232°C), 6-(2-cyano-3-chlorphenoxy)-4-methyl-3-carbolin-3-carbonsyre- isopropylester (smeltepunkt 230 - 232°C), 6-(2-cyano-2-fluorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-10 isopropylester (smeltepunkt 175°C), 6-(2-cyano-3-fluorphenoxy)-4-methoxymethyl-β-carbo1in-3-carbonsyre- isopropylester (smeltepunkt 208°C), 15 6-(2-isopropoxycarbonylphenoxy)-4-methoxymethyl-3-carbolin-3- carbonsyreisopropylester (smeltepunkt 145°C), 6-(2-t-butoxycarbonylphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyreisopropylester 20 (smeltepunkt 136°C), 6-(4-fluor-2-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-isopropylester, 6-(4-nitro-3-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- isopropylester, 6-(4-nitro-3-methylphenoxy)-4-methoxymethyl-p-carbolin-3- carbonsyreisopropylester, 2-4 DK 169702 B1 6-(2-nitro-3-chlorphenoxy)-4-methoxymethy1-β-carbolin-3-carbon-syrei sopropyle ster, 5 6-(2-nitro-3,5-dichlorphenoxy)-4-methoxymethy1-β-carbolin-3- carbonsyreisopropylester, 6-(2-nitrophenoxy)-4-methoxymethyl-(3-carbolin-3-carbonsyre-ethylester (smeltepunkt 153 - 155°C), 10 6-(4-nitro-3-methoxyphenoxy)-4-methoxymethyl-8-carbolin-3-carbon- syreethylester (smeltepunkt 192 - 203°C), 6- (4-nitro-2-methylphenoxy) -4-methoxymethyl-f3-carbolin-3-carbon-syreethylester 15 (smeltepunkt 184 - 185°C), 6- (4-nitro-2-chlorphenoxy) -4-methoxymethyl-|3-carbolin-3-carbon- syreethylester (smeltepunkt 195°C), 6-(4-nitro-3-methylphenoxy)~4-methoxymethyl-8-carbolin-3-carbon-2 0 syreethyle ster (smeltepunkt 183 - 184°C), 6-(4-ethoxycarbonylphenoxy)-4-methoxymethyl-3-carbolin-3-carbon- syreethylester (smeltepunkt 181°C), 25 DK 169702 B1 5 6-(4-methylsulfonylphenoxy)-4-methoxymethyl-3-carbolin-3-carbon-syreethyle ster (smeltepunkt 204 - 205°C), 10 5-(4-formylphenoxy)-4-methoxymethyl-0-carbolin-3-carbonsyreethyl- ester (smeltepunkt 190 - 192°C), 5-(2-nitro-4-chlorphenoxy)-4-methoxymethyl-0-carbolin-3-carbonsyre-ethylester 15 (smeltepunkt 160 - 162°C) , 5- (2-nitro-5-chlorphenoxy)-4-methoxymethyl-0-carbolin-3-carbon-syreethylester (smeltepunkt 155 - 170°C), 6- (4-nitro-2-methylphenoxy)-4-methoxymethyl-0-carbolin-3-carbon- 20 syreisopropylester, 6-(2-nitrophenoxy) -4-ethyl-0-carbolin-3-carbonsyreethylester, 6-(2-nitro-4-methoxyphenoxy)-4-methoxymethy1-3-carbolin-3-carbonsyr eisopropyles ter , 6-(4-nitro-3-methoxyphenoxy)-4-methoxymethyl-0-carbolin-3-carbon- 25 syreisopropylester, OK 169702 B1 6-(4-nitro-3-cyanophenoxy)-4-methoxymethyl-&-carbolin-3-carbon- syreisopropylester, 26 6- (2-nitro-4-methylphenoxy)-4-methoxymethyl-3-carbolin-3-carbon-syreisopropylester, 5 6-(2-methoxy-4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbon- syrei sopropyle ster, 10 6-(4-diethylsulfamoylphenoxy)-4-methoxymethyl-3-carbolin-3- carbonsyreethyle ster (smeltepunkt 179°C) og 6-(2-ethylsulfonylphenoxy)-4-methoxyinethyl-3-carbolin-3-carbon -syreethylester 15 (smeltepunkt 196 - 198°C).
EKSEMPEL 4.
5-(4-aminophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyreethyl-ester.
15 g 5-(4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-20 ethylester hydreres i 450 ml methanol:tetrahydrofuran (1:1) med 7,5 g palladium-på-carbon (10%) ved stuetemperatur under hydrogen-normaltryk. Efter filtrering og inddampning omkrystalliseres af ethanol, og man får 10,8 g (77% af det teoretiske) 5-(4-aminophenoxy) -4-methoxymethyl-3~carbolin-3-carbonsyreethylester med 25 smeltepunkt 222 - 224°C.
27 DK 169702 B1 På analog måde fremstilles: 5-(4-aminophenoxy)-4-methyl-3-carbolin-3-carbonsyreethylester (smeltepunkt 170 - 172°C), 5- (4-aminophenoxy)-4-ethyl-3-carbolin-3-carbonsyreethylester 5 (smeltepunkt 235°C), 6- (4-aminophenoxy)-4-me thyl-β-carbolin-3-carbonsyreethylester, 6-(4-aminophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-ethylester (smeltepunkt 204 - 234°C), 10 6- (4-amih:o-3-chlorphenoxy) -4-methoxymethyl-3-carbolin-3-carbonsyre- isopropylester, 6-(4-amino-3-methylphenoxy)-4-methoxymethyl-3-carbolin-3-carbon-syreisopropylester, 6- (2-amino-3-chlorphenoxy) - 4 -methoxymethy 1 -β - carbolin - 3 -carbonsyr e-15 isopropylester, 6-(2-amino-3,5-dichlorphenoxy)-4-methoxymethyl-3~carbolin-3-carbonsyreisopropylester, 5- (2-amino-5-chlorphenoxy) -4-methoxymethyl-3-carbolin-3-carbon-syreethylester, 20 6- (4-amino-2-methylphenoxy) -4-methoxymethyl-3-carbolin-3-carbon- syreisopropylester, 6- (4-fluor-2-aminophenoxy)-4-methoxymethyl-3-carbolin-3-carbon-syreisopropylester, 6-(4-amino-2-chlorphenoxy)-4-methoxymethyl-6-carbolin-3-carbonsyre- isopropylester, 28 DK 169702 B1 6-(2-amino-4-methoxyphenoxy)-4-methoxymethyl-6-carbolin-3-carbon-syre is opropylester, 5 6-(4-amino-3-methoxyphenpxy)-4-methoxymethy1-6-carbolin-3-carbon- syreisopropylester, 6-(4-amino-3-cyanophenoxy)-4-methoxymethyl-6-carbolin-3-carbonsyre-isopropylester, 6-(2-amino-4-methylphenoxy)-4-methoxymethyl-6-carbolin-3-carbon-10 syreisopropylester, 6 - (2 -methoxy .-4 -aminophenoxy) -4 -methoxymethy 1 -6 -carbolin-3 -carbon-syreisopropylester og 5-(4-aminophenoxy)-4-methoxymethyl-6-carbolin-3-carbonsyre-isopropylester 15 (smeltepunkt >250°C).
På principielt analog måde, men med Raney-nikkel som katalysator og tetrahydrofuran som opløsningsmiddel fremstilles: 5-(4-amino-3-chlorphenoxy)-4-methoxymethyl-6-carbolin-3-carbon-syreethylester 20 (smeltepunkt 202 - 204°C), 5- (4-amino-2-chlorphenoxy)-4-methoxymethyl-6-carbolin-3-carbon-syreethyle ster (smeltepunkt 204°C) og 6- (4-amino-2-chlorphenoxy)-4-methoxymethyl-6-carbolin-3-carbon- 2 5 syreethyle s t er (smeltepunkt 95 - 106°C).
29 DK 169702 B1 EKSEMPEL 5.
5-phenoxy-4-methoxymethyl-(3-carbolin-3-carbonsyreethylester.
978 mg 5-(4-aminophenoxy)-4-methoxymethyl-8-carbolin-3-carbonsyre-ethylester suspenderes i 2 ml vand og 10 ml af en 50% tetrafluor-borsyre. Efter afkøling til 0°C tilsættes dråbevis en opløsning 5 af 224 mg natriumnitrit i 2 ml vand, og der omrøres ved 0°C i 1/2 time. Derefter tilsættes ved samme temperatur 4 ml af en 60% phosphorundersyrling og 150 mg kobber(I)oxid, fortyndes med 10 ml vand og opvarmes i 1/2 time på dampbad. Efter indstilling af pH-værdien til 8 med soda og tilsætning af ammoniak ekstraheres 10 med eddikeester. Eddikeesterfasen inddampes, og remanensen kroma-tograferes over kiselgel med acetone:hexan (1:1) som eluerings-middel. Man får 540 mg (57% af det teoretiske) 5-phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyreethylester med smeltepunkt 174 - 176°C.
15 På analog måde fremstilles: 5-phenoxy-8-carbolin-3-carbonsyreethylester (smeltepunkt 246°C), 5-(3-chlorphenoxy) - 4 -methoxymethyl-8-carbolin-3-carbonsyreethyl-ester 20 (smeltepunkt 194 - 197°C), 5- (2-chlorphenoxy)-4-methoxymethyl-|3-carbolin-3-carbonsyreethyl-ester (smeltepunkt 175 - 177°C), 6- phenoxy-|3-carbolin-3-carbonsyreethylester ..
25 (smeltepunkt 241 - 242°C), '30 6-phenoxy-4-methyl-3-carbolin-3-carbonsyreethylester, DK 169702 B1 6-phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyreethylester (smeltepunkt 172 - 174°C), 6-(3-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyreiso-5 propylester (smeltepunkt 164°C), 6-(3-methylphenoxy)-4-methoxymethyl-3~carbolin-3-carbonsyreiso-propylester (smeltepunkt 170 - 174°C), 10 6- (3,5-dichlorphenoxy) -4-methoxymethyl-|3-carbolin-3-carbonsyreiso- propylester (smeltepunkt 210°C), 6-(2-methylphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-isopropylester 15 (smeltepunkt 165 - 170°C), 5- (2', 5-dichlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-ethylester (smeltepunkt 194 - 196°C), 6- (4-methoxyphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyreiso- 20 propylester, 6-(3-cyanophenoxy)-4-methoxymethy1-β-carbo1in-3-carbonsyreiso-propylester, 6-(3-methoxyphenoxy)-4-methoxymethyl-β-carbolin-3-carbonsyre- isopropylester, 31 DK 169702 B1 6-(4-methylphenoxy)-4-methoxymethyl-|3-carbolin-3-carbonsyre-isopropylester og 6-(2-methoxyphenoxy)-4-methoxymethyl-8-carbolin-3-carbonsyre-isopropylester.
5 EKSEMPEL 6.
5-(4-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-ethylester.
195 mg 5- (4-aminophenoxy) -4-methoxymethyl-(3-carbolin-3-carbonsyre-ethylester suspenderes i en blanding af 2 ml vand og 2 ml koncen-10 treret saltsyre, og efter afkøling til 0°C tilsættes dråbevis. en opløsning af 35 mg natriumnitrit i 0,5 ml vand. Efter endt tilsætning omrøres i 45 minutter ved 0°C, hvorved der opstår en lysegul opløsning. Dertil dryppes ved 0°C en opløsning, som forud er fremstillet ved tilsætning af 69 mg natriumsulfit i 0,5 ml vand 15 til 250 mg kobber(II)sulfat, 5 H^O og 87 mg kogsalt i 1 ml vand, frasugning af bundfaldet og opløsning i 0,5 ml koncentreret saltsyre! Efter endt tilsætning er der fremkommet en gul udfældning, og blandingen opvarmes på dampbad indtil afslutning af gasudviklingen. Derefter fortyndes med vand, indstillet alkalisk med 20 ammoniakopløsning og ekstraheres med eddikeester. Efter inddamp-ning af den organiske fase kromatograferes over kiselgel med methylenchlorid:ethanol (10:1) som elueringsmiddel. Man får 130 mg (55% af det teoretiske) 5-(4-chlorphenoxy)-4-methoxymethyl- 3-carbolin-3-carbonsyreethylester med smeltepunktet 207°C.
25 På analog måde fremstilles: 5-(4-chlorphenoxy)-4-methyl-£-carbolin-3-carbonsyreethylester, 32 DK 169702 B1 5- (2,4-dichlorphenoxy) -4-methoxymethyl-0-carbo lin-3-carbonsyre-ethylester (smeltepunkt 156 - 158°C), 6- (4-chlorphenoxy)-4-methyl-0-carbolin-3-carbonsyreethylester 5 (smeltepunkt 176 - 188°C), 6-(4-chlorphenoxy)-4-methoxymethy1-β-carbo1in-3-carbonsyre-ethylester (smeltepunkt 178°C), 6-(2,4-dichlorphenoxy)-4-methoxymethyl-|3-carbolin-3-carbonsyre-10 ethylester, 5- (4-jodphenoxy)-4-methoxymethyl-0-carbolin-3-carbonsyreethyl-ester (smeltepunkt 200°C), 6- (2-bromphenoxy)-4-methoxymethyl-0-carbolin-3-carbonsyre- 15 isopropylester (smeltepunkt 152 - 160°C), 6- (4-fluor-2-chlorphenoxy) -4-methoxymethyl-|3-carbolin- 3-carbonsyre-isopropylester (smeltepunkt 134 - 144°C), 20 6-(2,3-dichlorphenoxy)-4-methoxymethyl-β-carbolin-3-carbonsyrβ ίε op ropy le s ter (smeltepunkt 100 - 101°C), og 25 33 DK 169702 B1 6-(4-bromphenoxy)-4-methoxymethyl^-carbolin-3-carbonsyreethyl-ester (smeltepunkt 169 - 175°C)r 5 EKSEMPEL 7.
5-phenoxy-4-methoxymethyl“3-carbolin-3-carbonsyreisopropylester.
540 mg 5-phenoxy-4-methoxymethyl-β-carbolin-3-carbonsyreethylester 10 koges i 2 timer under tilbagesvaling i 30 ml isopropanol med 0,2 ml titan(IV)isopropylat. Efter inddampning tilsættes 0,5 n saltsyre og ekstraheres med eddikeester. Eddikeesterfasen tørres, filtreres og inddampes og digereres med diisopropylether. Man får 450 mg (82% af det teoretiske) 5-phenoxy-4-methoxymethy1-β-carbolin-15 3-carbonsyreisopropylester med smeltepunkt 207 - 209°C.
På analog måde fremstilles: 5-phenoxy-4-methyl^-carbolin-3-carbonsyreisopropylester, 5-(4-chlorphenoxy)-4-methyl^-carbolin-3-carbonsyreisopropyl-ester 20 (smeltepunkt 266 - 268°C), 5-(4-chlorphenoxy)-4-methoxymethyl-β-carbolin-3-carbonsyre isopropylester (smeltepunkt .216 - 218°C), - 34 DK 169702 B1 5-(4-nitrophenoxy)-4-methyl-3-carbolin-3-carbonsyreisopropyl-ester (smeltepunkt 262°C), 5- (4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- 5 isopropylester (smeltepunkt 207 - 209°C), 6~phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyreisopropylester (smeltepunkt 181°C), 6- (4-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-10 isopropylester (smeltepunkt 178 - 181°C), 6-(4-cyanophenoxy)-4-methoxymethy1 -3 -car b o 1 in - 3-carbonsyre- isopropylester (smeltepunkt 226 - 227°C), 15 6-(2-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- isopropylester (smeltepunkt 103 - 109°C), 6-(4-isopropoxycarbonylphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyreisopropylester 20 (smeltepunkt 167°C), 6- (3-chlor-4-nitrophenoxy) -*4-methoxymethyl-3-carbolin-3-carbonsyre-isopropylester (smeltepunkt 105 - 115°C), 6-(2r4-dichlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- 25 isopropylester (smeltepunkt 75 - 78°C), 35 DK 169702 B1 6-(4-fluorphenoxy)-4-methoxymethyl-B-carbolin-3-carbonsyre-isopropylester (smeltepunkt 104 - 116°C)·, 5- (3-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre- 5 isopropylester (smeltepunkt 187 - 189°C)-og 6- (3,4-dichlorphenoxy) -4-methoxymethyl-j3-carbolin-3-carbonsyre-isopropylester (smeltepunkt 66 - 68°C).
10 EKSEMPEL 8.
5-phenoxy-4-methoxymethyl-3“Carbolin-3-carbonsyreisopropylester.
2 g 5- (4-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-isopropylester bliver i 40 ml isopropanol hydreret med 200 mg palladium-på-carbon (10%) og 0,9 ml triethylamin ved stuetempera-15 tur under normalt hydrogen tryk. Efter filtrering fra katalysatoren, inddampning af filtratet og digerering af remanensen med diiso-propylether får man 1,4 g 5-phenoxy~4-methoxymethyl-3-carbolin- 3-carbonsyreisopropylester med smeltepunkt 201 - 203°C.
EKSEMPEL 9.
20 5-phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyre-t-butylester.
300 mg 5-phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyre opvarmes med 2 ml aminalester i 3 timer til 120°C, hvorved der opstår en opløsning. Efter fortynding med vand ekstraheres med eddikeester. Den organiske fase tørres, filtreres, inddampes og kromatograferes 36 DK 169702 B1 over kiselgel med acetone:hexan (1:1) som elueringsmiddel. Man får 130 mg 5-phenoxy-4-methoxymethyl-|3-carbolin--3-carbonsyre-t-butylester med et dekomponeringspunkt på 150°C.
På analog måde fremstilles: 5 5- (4-chlorphenoxy) -4--methoxymethyl-8-carbolin-3-carbonsyre-t- butylester (smeltepunkt 209 - 210°C), 6-(3-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-t-butylester 10 (smeltepunkt 159 - 160°C), 6- (2-cyanophenoxy) -4-methoxymethyl-(3-carbolin-3-carbonsyre-t- butylester (smeltepunkt 144°C), 6-(2-cyano-3-chlorphenoxy)-4-methoxymethyl-$--carbolin-3-carbonsyre-15 t-butylester (smeltepunkt 100°C), 6-(2,3-dichlorphenoxy)-4-methoxymethyl-!3--carbolin-3-carbonsyre-t-butylester (smeltepunkt 203 - 204°C), 20 6-(4“fluorphenoxy)-4-methoxymethyl-β-carbolin-3-carbonsyre-t- butylester (smeltepunkt 189 - 191°C), 5-(4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre-t- butylester 25 (smeltepunkt 221 - 222°C), 37 DK 169702 B1 6-(4-chlorphenoxy)-4-methyl-3-carbolin-3-carbonsyre-t-butylester og 6-phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyre-t-butylester.
5 EKSEMPEL 10 (Fremstilling af mellemprodukter) 5-phenoxy-4~methoxymethyl-3-carbolin-3-carbonsyre.
7,7 g 5-phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyreethylester opvarmes med 70 ml' 2 n natronlud, indtil der er opstået en klar 10 opløsning (2 timer). Derefter syrnes forsigtigt i varmen med 5 n saltsyre og omrøres i 15 minutter ved stuetemperatur. Efter frasugning og tørring over ve<^ 80°C får man 1,2 g (100% af det teoretiske) 5-phenoxy-4-methoxymethyl - 3-carbolin-3-carbonsyre.
15 På analog måde fremstilles: 5-(4-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre, 5- (4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre/ 6- (4-chlorphenoxy)-4-methyl-3-carbolin-3-carbonsyre, 6-phenoxy-4-methoxymethyl-3-carbolin-3-carbonsyre, 20 5-(4-nitrophenoxy)-4-methyl-3-carbolin-3-carbonsyre, 5-(4-nitrophenoxy)-3-carbolin-3-carbonsyre, 38 DK 169702 B1 6-phenoxy-3-carbolin-3-carbonsyre, 6-phenoxy-4-methyl-3-carbolin-3-carbonsyre, 6-(4-nitrophenoxy)-3-carbolin-3-carbonsyre, 6-(4-nitrophenoxy)-4-methyl-3-carbolin-3-carbonsyre, 5 6-(4-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre# 6- (4-bromphenoxy) -4-methoxymethyl-3-carbolin-3-carbonsyre, 6-(4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre, 6-(2-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre, 6-(2-methyl-4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre, 10 6- (4-morpholinosulfamoylphenoxy) -4-methoxymethyl-|3-carbolin-3- carbonsyre, 6-(4-methylsulfonylphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre, 6-(4-diethylsulfamoylphenoxy)-4-methoxymethyl-3-carbolin-3-carbon-syre, 15 6-(2-chlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre, 6-(4-cyanophenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre, 6-(4-fluorphenoxy)-3-carbolin-3-carbonsyre, 6-(2-chlor-4-nitrophenoxy)-4-methoxymethyl-3-carbolin-3~carbonsyre, 39 DK 169702 B1 6-(2,4-dichlorphenoxy)-4-methoxymethyl-3-carbolin-3-carbonsyre/ 6-(3-chlorphenoxy)-4-methoxymethyl-3“carbolin-3-carbonsyre/ 6- (2-cyanophenoxy) -4-methoxymethyl-0-carbolin-3-carbonsyre, 6- (2-cyano-3-chlorphenoxy) -4-xnethoxymethyl-3-carbolin-3-carbon-5 syre, 6-(2,3-dichlorphenoxy) “4-methoxymethyl-£-carbolin--3-carbonsyre og 6- (4-f luorphenoxy) -4-methoxymethylr|3-carbolin-3-carbonsyre.
Claims (4)
- 40 DK 169702 B1 Patentkrav.
- 1. Phenoxysubstituerede β-carboli nderivater med den almene 5 formel I R4 H hvor X er en oxadiazoly1 rest med formlen 15 O—N Z"3” R2 hvor R1 betyder lavere alkyl eller C3_7cykloalkyl eller X er 20 en C00R3-gruppe, hvor R3 betyder lavere alkyl, og R4 er hydrogen, lavere alkyl eller lavere alkoxyalkyl, og Ri optræder en eller flere gange og er hydrogen, halogen, 25 lavere alkyl, lavere alkoxy, Cj-^alkanoyl, cyano, nitro, lavere alkoxycarbonyl, SO2R6» hvor R6 betyder lavere alkyl, eller -NH2, idet X ikke er COOEt, når grupperne R* —og R4 betyder henholdsvis 5-phenoxy og methyl, eller 6-(4-methoxy-phenoxy) og methoxymethyl. Forbindelserne 35 5-(4-chlorphenoxy)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-methoxy-methyl-β-carbol in, 41 DK 169702 B1 5-phenoxy-4-methy 1 - 3- (3-ethyl-l,2,4-oxadiazol-5-yl)^-carbolin, 5- (4-ni trophenoxy) - 3- (3-et hyl -1,2,4-oxadiazol-5-yl)-£-carbolin, 5 5-(4-chlorphenoxy)-4-methy1-3-{3-ethy1-1,2,4-oxadiazol-5-yi)- β-carbol in, 6- phenoxy-4-raethy1 - 3- (3-ethyl-1,2,4-oxadiazol - 5-y 1 )-/S-carbolin, 10 6-(4-chlorphenoxy)-4-methy1-3-(3-ethyl-1,2,4-oxadiazol-5-y1)- β-carbolin, 6-(4-aminophenoxy)-4-methyl-3-(3-ethyl-1,2,4-oxadi azol-5-y1)-β-carbolin, 15 6-(4-chlorphenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4-oxadia-zol-5-y1)-β-carbolin, 6- (4-chlorphenoxy)-4-methoxymethyl-3-(3-cyklopropy1-1,2,4-oxa-20 diazol-5-yl )^-carbol in, 6-(4-methy1 sulfony1phenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4-oxadiazol-5-yl )^-carbolin, 25 6-(2-chlorphenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4-oxadia- zol-5-yl)^-carbolin, 6-(2,4-dichlorphenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4-oxadi-azol-5-y1)-β-carboli n, 30 5-(4-nitrophenoxy)-4-methoxymethyl-β-carboli n-3-carbonsyre-ethylester, 5- (4-ni tro-2-chlorphenoxy)-4-methoxymethyl-β-carboli n-3-car- 35 bonsyreethylester, 6- (4-ni trophenoxy)-4-methyl-β-carboli n-3-carbonsyreethyl ester, 42 DK 169702 B1 6-(4-ni trophenoxy)-4-methoxymethyl-Ø-carboli n-3-carbonsyre-ethylester, 5-(4-ami nophenoxy) -4-methoxymethy!-Ø-carbol in-3-carbonsyre-5 ethylester, 5-phenoxy-4-methoxymethy!-Ø-carbolin-3-carbonsyreethyl ester, 5- (3-chlorphenoxy) - 4-methoxymethyl -Ø-carbol i n-3-carbonsyre-10 ethylester, 5-(2-chl orphenoxy)-4-methoxymethyl-Ø-carboli n-3-carbonsyreethyl ester, 15 6-phenoxy-4-methoxymethyl-Ø-carboli n-3-carbonsyreethylester, 5-(4-chlorphenoxy)-4-methoxymethyl-0-carbol in-3-carbonsyre-ethylester, 20 5-(4-chlorphenoxy)-4-methyl-ø-carboli n-3-carbonsyreethyl ester, 5-(2,4-di chlorphenoxy)-4-methoxymethyl-Ø-carbolin-3-carbonsy-reethylester, 25 6-(4-chlorphenoxy)-4-methoxymethyl-Ø-carboli n-3-carbonsyre- ethylester, 5-(2-chlorphenoxy)-4-methoxymethy1-3-(3-ethy1-1,2,4-oxadiazol-5-yl)-0-carbolin, 30 5-(3-chlorphenoxy)-4-methoxymethy1-3-(3-ethy1-1,2,4-oxadiazol-5-yl)-Ø-carboli n, 5- (2-chlorphenoxy)-4-methoxymethyl-Ø-carbolin-3-carbonsyre- 35 isopropylester, 6- (2-nitrophenoxy)-4-methoxymethy1-Ø-carbolin-3-carbonsyre-isopropylester, 43 DK 169702 B1 6- (2-cyano-3-c hl orphenoxy) - 4-methoxymethy 1 -/3-c ar bol in-3-car-bonsyre-isopropyl ester, 6- (2-cyanophenoxy)- 4-methoxymethy 1 -β-carbol in-3-carbonsyre-5 isopropylester, 6-(4-acetylphenoxy)-4-methoxymethy!-3-(3-ethy1-1,2, 4-oxadia-zol - 5-y 1) -/S-carbol i n, 10 6-(3-chlorphenoxy)-4-methoxymethy1-β-carbol in-3-carbonsyre- isopropylester, 5-phenoxy-4-methoxymethyl - j8-carbolin-3-carbonsyrei sop ropy 1 -ester, 15 5-(4-chlorphenoxy)-4-methyl-β-carbol i n-3-carbonsyrei sopropy1-ester, 5- (4-chl orphenoxy) - 4-methoxymethyl - jS-carbolin-3-carbonsyreiso- 20 propylester, 6- (4-chlorphenoxy)-4-methoxymethyl-β-carbol in-3-carbonsyreiso-propylester, 25 5-(4-f1uorphenoxy)-4-methoxymethyl-β-carbolin-3-carbonsyreiso- propylester, 6-(3,4-dichlorphenoxy)-4-methoxymethy1-β-carboli n-3-carbonsy-reisopropylester, og 30 5-phenoxy-4-methoxymethyl-β-carbol in-3-carbonsyre-t-butylester.
- 3. Fremgangsmåde til fremstilling af forbindelser med den almene formel I, kendetegnet ved, at man 35 a) omsætter en forbindelse med den almene formel II DK 169702 B1 44 R4 H hvor Ri og R4 har den i krav 1 angivne betydning, med en forbindelse med formlen 2 ^N0H
- 10 R - NH2 hvor R2 har den i krav 1 angivne betydning, til en forbindelse med den almene formel I, hvor X betyder resten 15 -Ti| , N—J-ΈΓ 20 hvor R2 har den i krav 1 angivne betydning, b) omsætter en forbindelse med den almene formel III _ X c^°H X^°XdXXpT ^H2 κιΛ_/ /'O' t H 30 hvor Ri og R4 har den i krav 1 angivne betydning, med et car* bonsyreanhydrid (R2CO)20, hvor R2 har den i krav 1 angivne betydning, til en forbindelse med den almene formel I, hvor X er resten 35 DK 169702 B1 45 tf—O R2 hvor r2 har den i krav 1 angivne betydning, 5 c) omsætter en forbindelse med den almene formel IV R4 .✓s. .COOR3 HO [(-) 1 O (iv) f H hvor R3 og R4 har den i krav 1 angivne betydning, med en for-15 bindelse med formlen R1 Ha3—(^/ r1 20 '-' hvor Hal er halogen, Ri har den i krav 1 angivne betydning, og Ri' er en elektronfjernende substituent, og eventuelt derpå a) reducerer en nitrogruppe til aminogruppen og eventuelt des-25 aminerer den således fremkomne aminogruppe eller ombytter den med halogen, eller β) hvis Ri er halogen, dehalogenerer katalytisk eller 30 γ) omestrer eller forsæber en estergruppe. 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3540654 | 1985-11-13 | ||
| DE19853540654 DE3540654A1 (de) | 1985-11-13 | 1985-11-13 | Phenoxy-substituierte ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK543886D0 DK543886D0 (da) | 1986-11-13 |
| DK543886A DK543886A (da) | 1987-05-14 |
| DK169702B1 true DK169702B1 (da) | 1995-01-16 |
Family
ID=6286132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK543886A DK169702B1 (da) | 1985-11-13 | 1986-11-13 | Phenoxysubstituerede beta-carbolinderivater og fremgangsmåde til deres fremstilling |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4945090A (da) |
| EP (1) | EP0234173B1 (da) |
| JP (1) | JPH0699431B2 (da) |
| AT (1) | ATE90678T1 (da) |
| AU (1) | AU602497B2 (da) |
| CA (1) | CA1269377A (da) |
| DD (1) | DD254201A5 (da) |
| DE (2) | DE3540654A1 (da) |
| DK (1) | DK169702B1 (da) |
| ES (1) | ES2058064T3 (da) |
| FI (1) | FI84067C (da) |
| HU (1) | HU198046B (da) |
| IE (1) | IE61661B1 (da) |
| IL (1) | IL80618A (da) |
| NO (1) | NO163736C (da) |
| NZ (1) | NZ218244A (da) |
| PT (1) | PT83726B (da) |
| ZA (1) | ZA868631B (da) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3540653A1 (de) * | 1985-11-13 | 1987-05-14 | Schering Ag | Neue 3-oxadiazol- und 3-carbonsaeure-ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3540654A1 (de) * | 1985-11-13 | 1987-05-14 | Schering Ag | Phenoxy-substituierte ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3608089A1 (de) * | 1986-03-08 | 1987-09-10 | Schering Ag | Heteroaryl-oxy-ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3730667A1 (de) * | 1987-09-09 | 1989-03-23 | Schering Ag | Neue ss-carboline |
| DE3729370C2 (de) * | 1987-08-31 | 1995-04-20 | Schering Ag | Verfahren zur Herstellung von 4-Alkoxyalkyl-beta-carbolinen |
| DE4029389A1 (de) * | 1990-09-13 | 1992-03-26 | Schering Ag | Verfahren zur herstellung von (beta)-carbolin-derivaten |
| DE4109342A1 (de) * | 1991-03-19 | 1992-09-24 | Schering Ag | Selektive phenylierung von 5-hydroxy-ss-carbolinderivaten |
| US5350750A (en) * | 1991-04-27 | 1994-09-27 | Schering Aktiengesellschaft | β-carboline-3-hydroxyalkylcarboxylic acid ester derivatives, process for their production and their use in pharmaceutical agents |
| US5543519A (en) * | 1991-06-15 | 1996-08-06 | Schering Aktiengesellschaft | 3-aryl or 3-hetaryl-β-carbolines, their production and use in pharmaceutical agents |
| DE4120109A1 (de) * | 1991-06-15 | 1992-12-17 | Schering Ag | 3-aryl- oder 3-hetaryl-(beta)-carboline, deren herstellung und verwendung in arzneimitteln |
| AU2010204118B2 (en) | 2009-01-12 | 2012-12-20 | Icagen, Inc. | Sulfonamide derivatives |
| CA2804173C (en) | 2010-07-09 | 2015-01-13 | Pfizer Limited | Sulfonamide nav1.7 inhibitors |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57123180A (en) | 1980-12-17 | 1982-07-31 | Schering Ag | 3-substituted beta-carboline, manufacture and psychotropic drug containing same |
| DE3322895A1 (de) | 1983-06-23 | 1985-01-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neue ss-carboline, verfahren zur ihrer herstellung und ihre verwendung als arzneimittel (s) |
| DE3504045A1 (de) * | 1985-02-04 | 1986-08-07 | Schering AG, 1000 Berlin und 4709 Bergkamen | Verfahren zur herstellung von ss-carbolinen durch dehydrierung |
| DE3540654A1 (de) * | 1985-11-13 | 1987-05-14 | Schering Ag | Phenoxy-substituierte ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
-
1985
- 1985-11-13 DE DE19853540654 patent/DE3540654A1/de not_active Withdrawn
-
1986
- 1986-11-11 AT AT86730188T patent/ATE90678T1/de active
- 1986-11-11 DE DE8686730188T patent/DE3688594D1/de not_active Expired - Lifetime
- 1986-11-11 ES ES86730188T patent/ES2058064T3/es not_active Expired - Lifetime
- 1986-11-11 NZ NZ218244A patent/NZ218244A/xx unknown
- 1986-11-11 EP EP86730188A patent/EP0234173B1/de not_active Expired - Lifetime
- 1986-11-12 HU HU864678A patent/HU198046B/hu not_active IP Right Cessation
- 1986-11-12 NO NO864517A patent/NO163736C/no unknown
- 1986-11-12 DD DD86296211A patent/DD254201A5/de not_active IP Right Cessation
- 1986-11-12 CA CA000522771A patent/CA1269377A/en not_active Expired - Lifetime
- 1986-11-12 IL IL80618A patent/IL80618A/xx not_active IP Right Cessation
- 1986-11-12 PT PT83726A patent/PT83726B/pt not_active IP Right Cessation
- 1986-11-13 IE IE299686A patent/IE61661B1/en not_active IP Right Cessation
- 1986-11-13 JP JP61268799A patent/JPH0699431B2/ja not_active Expired - Lifetime
- 1986-11-13 ZA ZA868631A patent/ZA868631B/xx unknown
- 1986-11-13 DK DK543886A patent/DK169702B1/da not_active IP Right Cessation
- 1986-11-13 US US06/929,861 patent/US4945090A/en not_active Expired - Fee Related
- 1986-11-13 FI FI864619A patent/FI84067C/fi not_active IP Right Cessation
- 1986-11-13 AU AU65170/86A patent/AU602497B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU602497B2 (en) | 1990-10-18 |
| NO864517D0 (no) | 1986-11-12 |
| FI864619A0 (fi) | 1986-11-13 |
| EP0234173B1 (de) | 1993-06-16 |
| FI84067B (fi) | 1991-06-28 |
| ZA868631B (en) | 1987-06-24 |
| DD254201A5 (de) | 1988-02-17 |
| DK543886D0 (da) | 1986-11-13 |
| JPS62167780A (ja) | 1987-07-24 |
| HUT43067A (en) | 1987-09-28 |
| PT83726B (pt) | 1989-05-12 |
| NO163736B (no) | 1990-04-02 |
| EP0234173A2 (de) | 1987-09-02 |
| DE3540654A1 (de) | 1987-05-14 |
| JPH0699431B2 (ja) | 1994-12-07 |
| IE61661B1 (en) | 1994-11-16 |
| DK543886A (da) | 1987-05-14 |
| HU198046B (en) | 1989-07-28 |
| IE862996L (en) | 1987-05-13 |
| DE3688594D1 (de) | 1993-07-22 |
| ES2058064T3 (es) | 1994-11-01 |
| FI864619A7 (fi) | 1987-05-14 |
| NO163736C (no) | 1990-07-11 |
| FI84067C (fi) | 1991-10-10 |
| AU6517086A (en) | 1987-05-21 |
| ATE90678T1 (de) | 1993-07-15 |
| EP0234173A3 (en) | 1988-07-06 |
| PT83726A (en) | 1986-12-01 |
| IL80618A0 (en) | 1987-02-27 |
| NZ218244A (en) | 1990-05-28 |
| CA1269377A (en) | 1990-05-22 |
| IL80618A (en) | 1990-09-17 |
| NO864517L (no) | 1987-05-14 |
| US4945090A (en) | 1990-07-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |